The long range objective of this study is the development of gene therapy for treatment of hereditary disorders due to missing or defective clotting factors. Gene therapy would involve genetic modification of some of a patient's somatic cells so that they secrete a continuing supply of clotting factor and thus effect long-term cure of the disease. This project will develop the methodology in animal models using factors VIII and IX as model genes, retroviral vectors for gene transfer, and skin fibroblasts, vascular smooth muscle cells, and skeletal muscle cells as gene transfer targets. The goal of the project is to demonstrate production of levels of functional human clotting factors in the animal's circulation that would be curative if achieved in human patients. Initial testing of the techniques will be performed in mice and rats, with subsequent studies in hemophiliac dogs. Of particular concern is the development of techniques that would be suitable for use in humans, and efforts to be sure that there be no deleterious effects that would limit their use in humans. The specific aims include the development of retroviral vectors for efficient gene expression, testing of various somatic cell types and methods for gene introduction, examination of the duration of clotting factor synthesis from the genetically-modified cells, and the study of possible adverse effects of the procedures. It is suggested that the techniques developed in this project might have applications in the treatment of genetic diseases in general.